Caffeine use may cause or exacerbate anxiety, insomnia, panic attacks, hypertension, urinary incontinence, gastrointestinal disturbance, and problems in pregnancy. Some individuals become clinically dependent on caffeine and are unable to cut back or eliminate their caffeine use despite wanting to for medical reasons. For some individuals, caffeine withdrawal symptoms may produce significant distress that is incompatible with daily functioning and sometimes incapacitating. The co-ingestion of caffeine and alcohol has been implicated in increases in reckless behavior and alcohol-related injury, particularly among young adults. A series of studies in human volunteers will extend previous research investigating the clinical pharmacology of caffeine as a model system for understanding drug dependence by studying interactions of caffeine with alcohol and exploring the consequences and determinants of individual differences to caffeine effects. Three studies will investigate whether caffeine increases the reinforcing effects and self-administration of alcohol while concurrently assessing whether consuming caffeine and alcohol together produces greater decrements in perceived impairment compared to objective impairment. The first two of these studies will use acute dosing procedures to characterize interactions of caffeine and alcohol by studying the effects of a range of alcohol doses and caffeine:alcohol dose ratios. The third study will use self-administration and choice procedures to further investigate caffeine-alcohol interactions. These studies could have important implications for both education and regulatory policy about the co-ingestion of caffeine and alcohol. Another set of three studies will explore individual differences to caffeine effects. One study will explore whether individual differences in caffeine choice prospectively predict abuse potential of methlyphenidate, nicotine, and triazolam. Another study will determine whether individual differences in caffeine metabolism might account for the marked individual differences observed clinically in the severity of caffeine withdrawal symptoms. The third study will examine whether a family history of alcoholism is a determinant of individual differences in the inability to quit caffeine use among daily users of caffeine. These three studies will provide new information about biologic and genetic mechanisms of vulnerability to caffeine and substance dependence, with prevention and public education implications. In addition to the above studies, a clinical trial will be undertaken with caffeine dependent individuals who are distressed by their caffeine use and seeking treatment. The trial will compare an effective standard condition with a manual-only and a no-treatment condition. If the manual-only intervention is proven efficacious, it could be implemented in diverse clinical settings by health care providers with no expertise in caffeine dependence treatment. Overall, this project with caffeine as a model substance of dependence will provide information about pharmacological, behavioral, and genetic determinants substance abuse vulnerability, with important substance abuse prevention, treatment, and public education implications.